Induction of functional neutrophils from mouse fibroblasts by thymidine through enhancement of Tet3 activity

查看全文 作　　者：Buqing [1,2]Ye;Liuliu [1]Yang;Benyu [1,3]Liu;Nian [1,4]Liu;Dongdong [5]Fan;Huimu [1,4]Li;Lei [6]Sun;Ying [1]Du;Shuo [1]Wang;Yong [4,5]Tian;Zusen [1,4]Fan 机构地区：[1]Key Laboratory of Infection and Immunity of CAS,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China;[2]Department of Biomedical Engineering,College of Future Technology,Peking University,Beijing,100080,China;[3]Research Center of Basic Medicine,Academy of Medical Sciences,Zhengzhou University,Zhengzhou,450001,China;[4]University of Chinese Academy of Sciences,Beijing,100049,China;[5]Key Laboratory of RNA Biology,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China;[6]Core Facility Center,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China 出　　处：《Cellular & Molecular Immunology》索引2022年第19卷第5期,共15页 基　　金：supported by the National Key R&D Program of China (2020YFA0803501,2019YFA0508501,2021YFF0702802);the National Natural Science Foundation of China (82130088,31930036,81921003,31871494,92042302,91940305,32070533,81772646);the Beijing Natural Science Foundation (5192018);the Biological Resources Program of Chinese Academy of Sciences (KFJ-BRP-017);the Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB19030203). 摘　　要：Neutrophils are derived from bone marrow hematopoietic stem cells(HSCs)and are the largest population among circulating white blood cells in humans,acting as the first line of defense against invading pathogens.Whether neutrophils can be generated by transdifferentiation strategies is unknown.Here,we show that thymidine induces the conversion of mouse fibroblasts to neutrophils.Induced neutrophils(iNeus)showed antibacterial effects and did not undergo malignant transformation in vivo.Importantly,iNeu transplantation cured neutropenia in mice in vivo.Mechanistically,thymidine mediates iNeu conversion by enhancing Tet3 activity.Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils.Therefore,the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases. 关 键 词：FIBROBLASTS NEUTROPHILS THYMIDINE TRANSDIFFERENTIATION Tet3